Mechanisms and Duration of Immunity to SARS-CoV-2

SARS-CoV-2 的免疫机制和持续时间

• 批准号: 10706724
• 负责人: Scott Dexter Boyd
• 金额: $ 44万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-23 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706724
• 关键词: 2019-nCoV; Acute; Address; African American population; Agonist; Antibodies; Antigen Targeting; Attention; Award; B-Lymphocytes; Biopsy; Blood; COVID-19; COVID-19 diagnosis; COVID-19 patient; COVID-19 test; Cancer Patient; Caucasians; Cells; Clinical; Collaborations; Communities; Convalescence; Data; Data Set; Disease; Elderly; Evaluation; Female; Hispanic Americans; Human; Immune; Immune response; Immune system; Immunity; Immunologic Memory; Immunologics; Individual; Infection; Institution; Knowledge; Laboratories; Longitudinal Studies; Mucosal Immune Responses; Mucous Membrane; Nose; Patient Recruitments; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Physicians; Plasma; Plasma Cells; Populations at Risk; Prognosis; Protocols documentation; Research; Risk; Route; SARS-CoV-2 immune response; SARS-CoV-2 immunity; SARS-CoV-2 infection; Science; Serology; Severity of illness; Site; T cell response; T-Lymphocyte; Testing; Tissue Sample; Toll-like receptors; Translational Research; Translations; Vaccination; Validation; Viral Antigens; adaptive immune response; adaptive immunity; base; clinical development; cohort; data sharing; immune checkpoint blockade; interest; male; medically underserved; medically underserved population; member; mucosal site; novel therapeutic intervention; pandemic coronavirus; pandemic disease; patient population; research clinical testing; response; tool; vaccine candidate; vaccine trial; young adult

Primary immune deficiency disorders (PID) affect 1 in 2,000 individuals in the U.S., twice the prevalence of non-Hodgkin lymphoma. PID patients are at risk for severe COVID-19 and impaired responses to vaccination. Research into vaccine boosting in these individuals is clearly of importance for public health. Study of these patients, many of which have single-gene inborn causes for their phenotype, offers the valuable opportunity to correlate genotypes with immunological phenotypes in humans. Dr. Boyd will collaborate with Dr. Charlotte Cunningham-Rundles, a world expert in PID at the Mount Sinai School of Medicine in New York, to analyze the serological and B and T lymphocyte responses to vaccination and boosting using previously-collected plasma and peripheral blood mononuclear cells from a cohort of 142 PID patients whose disorders affect adaptive immune responses with a range of severity, and whose immunological phenotypes can include autoreactivity in addition to impaired protective immunity. The most common diagnosis in this cohort is Common Variable Immune Deficiency, (CVID). These patients generate suboptimal vaccine responses, but some can still mount specific antibody titers after vaccination. We will carry out an in-depth systemsimmunology characterization of serological responses and B cell and T cell populations in these patients, characterizing the frequencies, cellular phenotypes, B cell and T cell receptor sequences, and antigen epitopes targeted by antigen-specific B cells, using a panel of 14 different DNA-tagged SARS-CoV-2 variant antigen tetramers. Examination of T cell responses in the PID patients will include analysis of vaccine antigen-stimulated T cell frequencies and TCR sequences, and detailed flow cytometric immunophenotyping. These data will provide clinically relevant information about SARS-CoV-2 vaccination and boosting responses in PID patients to potentially contribute to clinical guidance as new Omicron variant-containing vaccine boosters are implemented, and should provide insights into the immunological genes, pathways and cell populations that contribute to adaptive immune responses and memory formation after mRNA vaccination in human patients.

原发性免疫缺陷病（PID）影响美国2,000人中的1人，是非霍奇金淋巴瘤的两倍PID患者面临严重COVID-19和疫苗接种反应受损的风险。 在这些人中加强疫苗接种的研究显然对公共卫生具有重要意义。对这些患者的研究提供了将人类基因型与免疫表型相关联的宝贵机会，其中许多患者的表型具有单基因先天原因。博伊德博士将与纽约西奈山医学院PID世界专家夏洛特·坎宁安-伦德尔博士合作，分析血清学和B和T淋巴细胞对疫苗接种的反应，并使用先前收集的血浆和外周血单核细胞从一组142名PID患者中进行加强免疫，这些患者的疾病影响了一系列严重程度的适应性免疫反应，并且其免疫表型除了受损的保护性免疫之外还包括自身反应性。该队列中最常见的诊断是常见变异型免疫缺陷（CVID）。这些患者产生了次优的疫苗应答，但有些患者在接种疫苗后仍能产生特异性抗体滴度。我们将对这些患者的血清学反应和B细胞和T细胞群体进行深入的系统免疫学表征，使用一组14种不同的DNA标记的SARS-CoV-2变体抗原四聚体来表征频率、细胞表型、B细胞和T细胞受体序列以及抗原特异性B细胞靶向的抗原表位。PID患者的T细胞应答检查将包括疫苗抗原刺激的T细胞频率和TCR序列的分析，以及详细的流式细胞术免疫表型分析。 这些数据将提供有关SARS-CoV-2疫苗接种和PID患者加强免疫反应的临床相关信息，以潜在地有助于实施新的含Omicron变体的疫苗加强剂的临床指导，并应提供对人类患者mRNA疫苗接种后有助于适应性免疫反应和记忆形成的免疫学基因、途径和细胞群的见解。